DNA virus infections in humans are the suspected cause of significant mortality from neoplastic diseases. DNA viruses also induce tumors in animals and in tissue culture transform normal cells to neoplastic cells that may or may not be tumorigenic. The pathogenicity of DNA viruses that leads to neoplasia is related to the function of virus genes that are expressed prior to viral DNA synthesis. We have been studying the functions of those early genes that control the tumor-inducing capacity of hamster cells transformed by seven different DNA viruses and have found that 1) during transformation, early virus genes convey specific levels of susceptibility or resistance to cellular immune rejection to neoplastic cells, 2) the susceptibility-resistance phenotype determines the neoplastic cell's tumor-inducing capacity and 3) the susceptibility-resistance phenotype is reflected in the ability of neoplastic cells to be lysed in vitro by natural killer cells and macrophages. Formation of hybrid cells between highly susceptible, weakly tumorigenic adenovirus (Ad)2-transformed cells and highly resistant, highly tumorigenic SV40-transformed cells shows that Ad2 early genes govern the tumorigenicity and susceptibility of the hybrid cells. Infection of resistant normal cells and SV40-transformed cells with Ad2 converts these resistant cells to cells that are highly susceptible to effector cell lysis; furthermore, expression of specific levels of 58K early Ad2 proteins in somatic cell hybrids seems to correlate with their level of susceptibility. Thus, the induction of susceptibility governs the phenotype of transformed cells that contain the early genes of susceptibility-inclucing Ad2; the expression of resistance (associated with high tumorigenicity) may be due to the inability of the early genes of highly tumorigenic DNA viruses to induce susceptibility. Based on these results, we believe that we are now defining those early gene functions that control the pathogenesis of these viruses in infected cells that express neoplastic potential.